Sex differences in methamphetamine toxicity in mice: Effect on brain dopamine signaling pathways
dopamine; mice; Psychiatry; Akt; 3; 2; 1-methyl-4-phenyl-1; Neurosciences & Neurology; Endocrinology & Metabolism; cell-death; activation; neurotoxicity; induced; rat striatum; kinase; striatum; Methamphetamine; evoked striatal dopamine; neurotoxicity; cd-1; element-binding protein; Sex difference; transporter function; 6-tetrahydropyridine mice
Mate mice were reported to display greater methamphetamine-induced neurotoxicity than females. The present study evaluated the involvement of phosphatidylinositol-3 kinase (PI3K)/Akt and extracellular signal-regulated kinase (ERK1/2) pathways in this sex-dependent methamphetamine toxicity. Intact female and male mice were administered methamphetamine (20 or 40 mg/kg) and euthanized a week later. Dopamine transporter (DAT) and vesicular monoamine transporter 2 (VMAT2) autoradiography in the lateral striatum showed a greater sensitivity in male mice treated with 20 mg/kg methamphetamine compared to female mice. Striatal dopamine concentration and DAT autoradiography showed a more extensive depletion in male mice given 40 mg/kg methamphetamine compared to female mice. Mice administered 40 mg/kg methamphetamine showed no sex difference in striatal VMAT2 autoradiography. In the substantia nigra, DAT specific binding was decreased only in male mice treated with 40 mg/kg methamphetamine and DAT mRNA levels decreased in methamphetamine-treated female and male mice. Methamphetamine-treated male mice presented a dose-dependent decrease of VMAT2 mRNA levels. Methamphetamine reduced insulin-like growth factor 1 receptor levels in females at both methamphetamine doses tested whereas it elevated G protein-coupled estrogen receptor 1 (GPER1) only in male mice. Phosphorylated Akt levels decreased only in male mice treated with 40 mg/kg methamphetamine. Glycogen synthase kinase 30 levels were reduced in male mice at both methamphetamine doses tested and in females receiving 40 mg/kg. Bcl-2 Levels were increased in male mice treated with methamphetamine, whereas ERK1/2 and BAD levels were unchanged. These results implicate some of the signaling pathways associated with the sex differences in methamphetamine-induced toxicity. (C) 2011 Elsevier Ltd. All rights reserved.
Bourque M; Liu B; Dluzen D E; Di Paolo T
Psychoneuroendocrinology
2011
2011-08
Journal Article or Conference Abstract Publication
<a href="http://doi.org/10.1016/j.psyneuen.2010.12.007" target="_blank" rel="noreferrer noopener">10.1016/j.psyneuen.2010.12.007</a>
Sex and temporally-dependent effects of methamphetamine toxicity on dopamine markers and signaling pathways
dopamine; Akt; Neurosciences & Neurology; Pharmacology & Pharmacy; gene-expression; estrous-cycle; striatum; protein-phosphorylation; markers; glycogen-synthase kinase-3-beta; Methamphetamine; Sex difference; evoked striatal dopamine; induced neurotoxicity; monoamine; neuronal apoptosis; neurotoxicity; physiological functions; terminal; transporters
Methamphetamine induces a greater neurodegenerative effect in male versus female mice. In order to investigate this sex difference we studied the involvement of Akt and extracellular signal-regulated kinase (ERK1/2) in methamphetamine toxicity as a function of time post-treatment (30 min, 1 and 3 days). Methamphetamine-induced decreases in dopamine concentrations and dopamine transporter (DAT) specific binding in the medial striatum were similar in female and male mice when evaluated 1 day post-methamphetamine (40 mg/kg). At 3 days post-methamphetamine, striatal dopamine concentration and DAT specific binding continued to decline in males, whereas females showed a recovery with increases in dopamine content and DAT specific binding in medial striatum at day 3 versus day 1 post-methamphetamine. The reduction in striatal vesicular monoamine transporter 2 specific binding observed at 1 and 3 days post-methamphetamine showed neither a sex- nor temporal-dependant effect. Under the present experimental conditions, methamphetamine treatments had modest effects on dopamine markers measured in the substantia nigra. Proteins assessed by Western blots showed similar reductions in both female and male mice for DAT proteins at 1 and 3 days post-methamphetamine. An increase in the phosphorylation of striatal Akt (after 1 day), glycogen synthase kinase 3 beta (at 1 and 3 days) and ERK1/2 (30 min post-methamphetamine) was only observed in females. Striatal glial fibrillary acidic protein levels were augmented in both females and males at 3 days post-methamphetamine. These results reveal some of the sex- and temporally-dependent effects of methamphetamine toxicity on dopaminergic markers and suggest some of the signaling pathways associated with these responses. (C) 2012 Elsevier Ltd. All rights reserved.
Bourque M; Dluzen D E; Di Paolo T
Neuropharmacology
2012
2012-06
Journal Article or Conference Abstract Publication
<a href="http://doi.org/10.1016/j.neuropharm.2012.02.009" target="_blank" rel="noreferrer noopener">10.1016/j.neuropharm.2012.02.009</a>
Neuroprotective actions of sex steroids in Parkinson's disease
parkinsons-disease; Neuroprotection; MPTP; Akt; Neurosciences & Neurology; Endocrinology & Metabolism; estrogen-receptor-alpha; rat cortical-neurons; methamphetamine-induced neurotoxicity; activated protein-kinase; mptp-induced neurotoxicity; glycogen-synthase kinase-3-beta; Androgens; estrogen; induced cell-death; MAPK/ERK; Methamphetamine; nigrostriatal dopaminergic system; Progesterone; regulates bcl-2 expression; Sex difference; vesicular monoamine transporter
The sex difference in Parkinson's disease, with a higher susceptibility in men, suggests a modulatory effect of sex steroids in the brain. Numerous studies highlight that sex steroids have neuroprotective properties against various brain injuries. This paper reviews the protective effects of sex hormones, particularly estradiol, progesterone and androgens, in the 1-methyl-4-phenyl-1,2,3,6-tetrahydropyridine (MPTP) animal model of Parkinson's disease as compared to methamphetamine toxicity. The molecular mechanisms underlying beneficial actions of sex steroids on the brain have been investigated showing steroid, dose, timing and duration specificities and presently focus is on the dopamine signaling pathways, the next frontier. Both genomic and non-genomic actions of estrogen converge to promote survival factors and show sex differences. Neuroprotection by estrogen involves activation of signaling molecules such as the phosphatidylinositol-3 kinase/Akt and the mitogen-activated protein kinase pathways. Interaction with growth factors, such as insulin-like growth factor 1, also contributes to protective actions of estrogen. (C) 2009 Elsevier Inc. All rights reserved.
Bourque M; Dluzen D E; Di Paolo T
Frontiers in Neuroendocrinology
2009
2009-07
Journal Article or Conference Abstract Publication
<a href="http://doi.org/10.1016/j.yfrne.2009.04.014" target="_blank" rel="noreferrer noopener">10.1016/j.yfrne.2009.04.014</a>